Obesity is a serious health problem in the US and Western societies, and it has been reported that nearly one out of four Americans is obese. Leptin is a protein secreted by adipose tissue that has been implicated in the regulation of food intake and energy homeostasis. Mice lacking leptin or a functional leptin receptor (ObR) are grossly obese and show other physiological defects, and leptin administration to mice leads to a decrease in adipose tissue through reduced food intake and increased energy expenditure. However, the exact mechanisms underlying the effects of leptin are not well understood. In the experiments proposed here, we will attempt to elucidate the mechanisms by which leptin exerts its effects on food intake and energy homeostasis. The role that tyrosine phosphorylation of the ObR plays in mediating the effects of leptin will be examined through the creation of transgenic mice expressing mutant ObRs in which the intracellular tyrosines have been mutated. In addition, the effects of leptin on the activity of specific neuronal populations will be measured. Mice containing specific neuronal subtypes labeled with GFP will be created, and patch-clamp technology will be utilized to measure the effects of leptin on activity of the neurons. These experiments should greatly further our understanding of the effects of leptin, and may provide new avenues for intervention into the prevention and treatment of obesity.